AU600248B2 - N- (butenyl-substituted) azaheterocyclic carboxylic acids - Google Patents
N- (butenyl-substituted) azaheterocyclic carboxylic acids Download PDFInfo
- Publication number
- AU600248B2 AU600248B2 AU67193/87A AU6719387A AU600248B2 AU 600248 B2 AU600248 B2 AU 600248B2 AU 67193/87 A AU67193/87 A AU 67193/87A AU 6719387 A AU6719387 A AU 6719387A AU 600248 B2 AU600248 B2 AU 600248B2
- Authority
- AU
- Australia
- Prior art keywords
- derivatives
- substituted
- group
- lower alkyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 150000001735 carboxylic acids Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 imidazolyl pyrazolyl Chemical group 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- MPMBRWOOISTHJV-UHFFFAOYSA-N but-1-enylbenzene Chemical class CCC=CC1=CC=CC=C1 MPMBRWOOISTHJV-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 230000001624 sedative effect Effects 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- 206010039897 Sedation Diseases 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 230000036280 sedation Effects 0.000 claims 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- QTDZOWFRBNTPQR-UHFFFAOYSA-N guvacine Chemical compound OC(=O)C1=CCCNC1 QTDZOWFRBNTPQR-UHFFFAOYSA-N 0.000 description 22
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910004298 SiO 2 Inorganic materials 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 7
- XJLSEXAGTJCILF-UHFFFAOYSA-N nipecotic acid Chemical compound OC(=O)C1CCCNC1 XJLSEXAGTJCILF-UHFFFAOYSA-N 0.000 description 7
- DYPLDWLIOGXSSE-UHFFFAOYSA-N guvacoline Chemical compound COC(=O)C1=CCCNC1 DYPLDWLIOGXSSE-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229910052681 coesite Inorganic materials 0.000 description 5
- 229910052906 cristobalite Inorganic materials 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229910052682 stishovite Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229910052905 tridymite Inorganic materials 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- TXQKSMSLZVKQBI-UHFFFAOYSA-N 1-(4,4-diphenylbut-3-enyl)-3-piperidinecarboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 TXQKSMSLZVKQBI-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000012345 traction test Methods 0.000 description 3
- DRTQKVNJIVIKMM-UHFFFAOYSA-N (2-methylphenyl)-(3-methylthiophen-2-yl)methanol Chemical compound C1=CSC(C(O)C=2C(=CC=CC=2)C)=C1C DRTQKVNJIVIKMM-UHFFFAOYSA-N 0.000 description 2
- NNHFTYXKYCVPFN-UHFFFAOYSA-N 1-(4,4-diphenylbut-3-enyl)-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound C1C(C(=O)O)=CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 NNHFTYXKYCVPFN-UHFFFAOYSA-N 0.000 description 2
- ZEUXGNDNEDPRFR-UHFFFAOYSA-N 1-[4-(1-methylpyrrol-2-yl)-4-phenylbut-3-enyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid;hydrochloride Chemical compound Cl.CN1C=CC=C1C(C=1C=CC=CC=1)=CCCN1CC(C(O)=O)=CCC1 ZEUXGNDNEDPRFR-UHFFFAOYSA-N 0.000 description 2
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 238000011765 DBA/2 mouse Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000016285 Movement disease Diseases 0.000 description 2
- 208000021642 Muscular disease Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical class OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- ZWALOEQHJRUTKM-UHFFFAOYSA-N methyl 1,2,3,6-tetrahydropyridine-5-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1=CCCNC1 ZWALOEQHJRUTKM-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000010825 rotarod performance test Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- MHZJWHBLWIWKAW-UHFFFAOYSA-N (2-methylphenyl)-(3-methylthiophen-2-yl)methanone Chemical compound C1=CSC(C(=O)C=2C(=CC=CC=2)C)=C1C MHZJWHBLWIWKAW-UHFFFAOYSA-N 0.000 description 1
- YYCQXFAEQPFCBP-UHFFFAOYSA-N (2-methylphenyl)-pyridin-4-ylmethanol Chemical compound CC1=CC=CC=C1C(O)C1=CC=NC=C1 YYCQXFAEQPFCBP-UHFFFAOYSA-N 0.000 description 1
- ZJTMSGIHLUTOCY-IBGZPJMESA-N (2s)-1-[4-(3-methylthiophen-2-yl)-4-phenylbut-3-enyl]piperidine-2-carboxylic acid Chemical compound C1=CSC(C(=CCCN2[C@@H](CCCC2)C(O)=O)C=2C=CC=CC=2)=C1C ZJTMSGIHLUTOCY-IBGZPJMESA-N 0.000 description 1
- VYKBUUWZZKFJRP-GOSISDBHSA-N (3r)-1-[4-(1-methylpyrrol-2-yl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid Chemical compound CN1C=CC=C1C(C=1C=CC=CC=1)=CCCN1C[C@H](C(O)=O)CCC1 VYKBUUWZZKFJRP-GOSISDBHSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- XMNPCAUUGPBOGR-UHFFFAOYSA-N 1-(4-phenyl-4-pyridin-2-ylbut-3-enyl)-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound C1C(C(=O)O)=CCCN1CCC=C(C=1N=CC=CC=1)C1=CC=CC=C1 XMNPCAUUGPBOGR-UHFFFAOYSA-N 0.000 description 1
- BPJDQKQDIGCICH-UHFFFAOYSA-N 1-(4-phenyl-4-pyridin-4-ylbut-3-enyl)piperidine-3-carboxylic acid;hydrochloride Chemical compound Cl.C1C(C(=O)O)CCCN1CCC=C(C=1C=CN=CC=1)C1=CC=CC=C1 BPJDQKQDIGCICH-UHFFFAOYSA-N 0.000 description 1
- ZASZCKQEHQQNHY-UHFFFAOYSA-N 1-(4-phenyl-4-thiophen-2-ylbut-3-enyl)piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CS1 ZASZCKQEHQQNHY-UHFFFAOYSA-N 0.000 description 1
- RWMGCKJBGXUOOW-UHFFFAOYSA-N 1-[4-(1-methylimidazol-2-yl)-4-phenylbut-3-enyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound CN1C=CN=C1C(C=1C=CC=CC=1)=CCCN1CC(C(O)=O)=CCC1 RWMGCKJBGXUOOW-UHFFFAOYSA-N 0.000 description 1
- IMNLKJKLBQJOAF-UHFFFAOYSA-N 1-[4-(1-methylimidazol-4-yl)-4-phenylbut-3-enyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound CN1C=NC(C(=CCCN2CC(=CCC2)C(O)=O)C=2C=CC=CC=2)=C1 IMNLKJKLBQJOAF-UHFFFAOYSA-N 0.000 description 1
- XUYBSZVSDGUVNV-UHFFFAOYSA-N 1-[4-(1-methylpyrazol-3-yl)-4-phenylbut-3-enyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound CN1C=CC(C(=CCCN2CC(=CCC2)C(O)=O)C=2C=CC=CC=2)=N1 XUYBSZVSDGUVNV-UHFFFAOYSA-N 0.000 description 1
- OOQGHNKUQCGJLT-UHFFFAOYSA-N 1-[4-(1-methylpyrrol-2-yl)-4-phenylbut-3-enyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound CN1C=CC=C1C(C=1C=CC=CC=1)=CCCN1CC(C(O)=O)=CCC1 OOQGHNKUQCGJLT-UHFFFAOYSA-N 0.000 description 1
- VYKBUUWZZKFJRP-UHFFFAOYSA-N 1-[4-(1-methylpyrrol-2-yl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid Chemical compound CN1C=CC=C1C(C=1C=CC=CC=1)=CCCN1CC(C(O)=O)CCC1 VYKBUUWZZKFJRP-UHFFFAOYSA-N 0.000 description 1
- GMRNAHWJWVGTQL-UHFFFAOYSA-N 1-[4-(2-methylphenyl)-4-pyridin-3-ylbut-3-enyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound CC1=CC=CC=C1C(C=1C=NC=CC=1)=CCCN1CC(C(O)=O)=CCC1 GMRNAHWJWVGTQL-UHFFFAOYSA-N 0.000 description 1
- LJFNELLBTQVHFT-UHFFFAOYSA-N 1-[4-(2-methylphenyl)-4-pyridin-4-ylbut-3-enyl]piperidine-3-carboxylic acid Chemical compound CC1=CC=CC=C1C(C=1C=CN=CC=1)=CCCN1CC(C(O)=O)CCC1 LJFNELLBTQVHFT-UHFFFAOYSA-N 0.000 description 1
- FDRIRJKYTLXASG-UHFFFAOYSA-N 1-[4-(furan-2-yl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CO1 FDRIRJKYTLXASG-UHFFFAOYSA-N 0.000 description 1
- SMEBIIOHFZYHDS-UHFFFAOYSA-N 2-(4-chloro-1-phenylbut-1-enyl)-1-ethylpyrrole Chemical compound CCN1C=CC=C1C(=CCCCl)C1=CC=CC=C1 SMEBIIOHFZYHDS-UHFFFAOYSA-N 0.000 description 1
- YODZFAHPPAGHEM-UHFFFAOYSA-N 2-(4-chloro-1-phenylbut-1-enyl)-1-methylpyrrole Chemical compound CN1C=CC=C1C(=CCCCl)C1=CC=CC=C1 YODZFAHPPAGHEM-UHFFFAOYSA-N 0.000 description 1
- LWHKYUXECNPJRA-UHFFFAOYSA-N 2-[4-bromo-1-(2-methylphenyl)but-1-enyl]-3-methylthiophene Chemical compound C1=CSC(C(=CCCBr)C=2C(=CC=CC=2)C)=C1C LWHKYUXECNPJRA-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- BSQKBHXYEKVKMN-UHFFFAOYSA-N 3-methylthiophene-2-carbaldehyde Chemical compound CC=1C=CSC=1C=O BSQKBHXYEKVKMN-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- GOAZBOMELZSHSB-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)C=1NC=CC1.C(C1=CC=CC=C1)(=O)C=1N(C=CC1)CC Chemical compound C(C1=CC=CC=C1)(=O)C=1NC=CC1.C(C1=CC=CC=C1)(=O)C=1N(C=CC1)CC GOAZBOMELZSHSB-UHFFFAOYSA-N 0.000 description 1
- ITZHCIPFEPEGNN-UHFFFAOYSA-N C1(CC1)C(O)(C1=CC=CC=C1)C=1N(C=CC1)C.BrCCC=C(C1=CC=CC=C1)C=1N(C=CC1)C Chemical compound C1(CC1)C(O)(C1=CC=CC=C1)C=1N(C=CC1)C.BrCCC=C(C1=CC=CC=C1)C=1N(C=CC1)C ITZHCIPFEPEGNN-UHFFFAOYSA-N 0.000 description 1
- YXESKLMSACUFEK-UHFFFAOYSA-L CC(C=CC=C1)=C1C(C1=CC=NC=C1)=O.O[Cr](Cl)(=O)=O.C1=CC=NC=C1 Chemical compound CC(C=CC=C1)=C1C(C1=CC=NC=C1)=O.O[Cr](Cl)(=O)=O.C1=CC=NC=C1 YXESKLMSACUFEK-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
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- 241000906446 Theraps Species 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- 241000009298 Trigla lyra Species 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- XBPLFVPDGFWMHB-UHFFFAOYSA-N bis[2-(1-methylpyrrol-2-yl)phenyl]methanone Chemical compound CN1C=CC=C1C1=CC=CC=C1C(=O)C1=CC=CC=C1C1=CC=CN1C XBPLFVPDGFWMHB-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- LFGCOQHXVIDCTC-UHFFFAOYSA-N cyclopropyl-(1-methylpyrrol-2-yl)-phenylmethanol Chemical compound CN1C=CC=C1C(O)(C=1C=CC=CC=1)C1CC1 LFGCOQHXVIDCTC-UHFFFAOYSA-N 0.000 description 1
- LNWDMROPXBKRKW-UHFFFAOYSA-N cyclopropyl-(furan-2-yl)-phenylmethanol Chemical compound C=1C=COC=1C(C=1C=CC=CC=1)(O)C1CC1 LNWDMROPXBKRKW-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- JTBGGUKKCQWTBL-UHFFFAOYSA-N ethyl 1-(4-phenyl-4-pyridin-4-ylbut-3-enyl)piperidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CCCN1CCC=C(C=1C=CN=CC=1)C1=CC=CC=C1 JTBGGUKKCQWTBL-UHFFFAOYSA-N 0.000 description 1
- UXKBSXZPXHLNOH-UHFFFAOYSA-N ethyl 1-[4-(1-methylpyrrol-2-yl)-4-phenylbut-3-enyl]piperidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CN1C UXKBSXZPXHLNOH-UHFFFAOYSA-N 0.000 description 1
- IQOJIJYCIXIWCC-UHFFFAOYSA-N ethyl 1-[4-(2-methylphenyl)-4-pyridin-4-ylbut-3-enyl]piperidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CCCN1CCC=C(C=1C(=CC=CC=1)C)C1=CC=NC=C1 IQOJIJYCIXIWCC-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- CRLNTRZMHKNJSR-UHFFFAOYSA-N furan-2-yl(phenyl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CO1 CRLNTRZMHKNJSR-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- SKFLCXNDKRUHTA-UHFFFAOYSA-N phenyl(pyridin-4-yl)methanone Chemical compound C=1C=NC=CC=1C(=O)C1=CC=CC=C1 SKFLCXNDKRUHTA-UHFFFAOYSA-N 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
01- i 0 1-1 0 248 FORM 10 SPRUSON &8 FERGUSON COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICAT!ON
(ORIGINAL)
FOR OFFICE USE: Class Int. Class Complete Specification Lodged: Accepted: a o z,0 Published: Priority: Related Art: Thi! ometnt contains the Sar.er.ts made i" 1 1 r ii'i Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: Novo Industri A/S Novo Alle, 2880 Bagsvaerd, Denmark URSULA SONNEWALD Spruson Ferguson, Patent Attorneys, Level 33 St Martins Tower, 31 Market Street, Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: N fuI- +uACdt) q k eipcyc ic CarE-c Ic-W The following statement is a full description of this invention, including the best method of, performing it known to us SBR:JMA:220W TON/VMN, 1986-12-16, 3o, D-363, IL 3020.200 00 00 0 0 o 0 0 0000 0 o 00 0 000000 o 0 00 0 0 0000 0 OU 0 000 0 00 0 g0o 0 0a a 00 t&s- (t3u-ery su zvlc)aqhetry ca.rboq(cyi c( I-, P oe4~R i ei Dr- at1
ABSTRACT
Phenylbutene derivatives having optionally substituted phenyl and pyrrolyl, furanyl, pyridinyl, pyrazinyl, irnidazolyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or alkyithienyl in the 4-position and 3-carboxypiperid-1-yl, 3carboxytetrahydropyrid-l-yl or 3-carboxyrnethylpyrrolidin-l-yl in the 1-position potentiate GABA'ergic neurotransmissioni.
E:
1A SUMMARY OF THE INVENTION The present Invention relates to phenylbuten derivatives of the general formula I
R
1
-C-CH-CH
2
-CH
2
-R
3
(I)
12
R
wherein R represents phenyl optionally substituted by one, two or more substituents selected from the group consisting of halogen, lower alkyl, and lower alkoxy, R 2 represents pyrrolyl, furanyl, pyridinyl, pyrazinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or piperazinyl each of which may be substituted by one, two or 0o oo more substituents selected from the group consisting of halogen, lower 00 2 o0.o alkyl and lower alkoxy or R represents a thienyl group substituted by a 0 0 0 o° loweralkyl group which substituted thienyl group may be further substituted 000000 o 0 o by one, two or more substituents selected from the group consisting of 00 o0,15 halogen, lower alkyl, and lower alkoxy, and R represents 0 o°0 3-carboxypiperid-l-yl, 3-carboxy-l ,2,5,6-tetrahydropyrid-l-yl or 0000 3-carboxymethylpyrrolidin-l-yl, the corresponding amides or lower alkyl esters, or salts thereof. The compounds have interesting and valuable pharmacological properties.
o0: 20 BACKGROUND OF THE INVENTION 048 In the last decade, intensive pharmacological research concerning y-aminobutyric acid (hereinafter designated GABA), a neurotransmitter in the central nervous system, has taken place.
Increased GABA'ergic activity is useful in the treatment of anxiety, pain, epilepsy and muscular and movement disorders. Furthermore, these compounds can be used as sedatives.
511U ToN/VMN, 1986-12-16, 3o, D-363, ILII\, 3020.200 In U.S. patent specification No. 4,383,999 (Srithkline Beckmann Corporation) some derivatives of N-(4phenyl-3-butenyl)azaheterocyclic carboxylic acids which have, furthermore, inter alia, phenyl, p-fluorophenyl, cyclohexyl or thienyl in the 4- position, are described.
According to J.Pharm.Exp.Therap. 228 (1984), 109 et seq., N-(4,4-diphenyl--3-butenyl)nipecotic acid (designated SK&F 89976A), N-(4,4-diphenyl-3-butenyl)guvacine (designated SK&F 100330A), N-(4,4-diphenyl-.3-butenyl)-f3-homoproline (designated SK&F 100561) and N-(4--phenyl-4-(2-thienyl)-3-butenyl)nipecotic acid (designated SI &F 100604J) are orally active inhibitors of GABA uptake.
00000 ao0 00 0 0 DETAILED PRACTICE OF THIS INVENTION 00 0000 It has now been found that novel compounds of the general formula I stated in Claim 1, below, exhibit GABA uptake 0n 0 0 inhibitory properties and possess useful pharmacological 0 o~ properties on the central nervous system, a selective enhancement of GABA activity. Surprisingly, these effects are 0 V 4superior to those of previously known compounds. Compounds of formula I may be used for -treatment of, for example, pain, anxiety, epilepsy, certain muscular and movement disorders and o other neurological disorders and as sedatives and hypnotics.
Herein pyrroly. is 2-pyrrolyl or 3-pyrrolyl, furanyl is 2-furanyl or 3-furanyl, pyridinyl (pyridyl) is 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrazinyl is 2-pyrazinyl or 3pyrazinyl.. imidazolyl is 2-imidazolyl, 4-imidazolyl or imidazolyl, pyrazolyl is 3-pyrazolyl, 4-pyrazolyl or pyrazolyl, pyrimidinyl is 2-pyrimidinyl, 4-pyriridinyl, pyrimidinyl or 6-pyrimidinyl, pyrrolidinyl is 2"-pyrrolidinyl or 3-pyrrolidinyl, te-trahydrofuranyl is 2-tetrahydrofuranyl or 3tetrahydrofuranyl, piperidinyl (piperidyl) is 2-piperidyl, 3piperidyl or 4-piperidyl, piper"azinyl is 2-piperazinyl, 3piperazinyl or 4-piperazinyl and thienyl is 2-thienyl or 3- ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 thianyl. Furthermore, halogen is, preferably, chioro, bromo and fluoro. The lower alkyl group contains less than 8 carbon atoms, preferably less than 5 carbon atoms, and some preferred alkyl groups are methyl and ethyl. The lower alkoxy group contains less than 8 carbon atoms, preferably less than carbon atoms, and some prfered alko/xy gro ps are methoxy and ethoxy. Preferably, i-c-wer alk.'l)h~y is 3-met~hylthien-2-yl.
Specific examples of substituted groups R 1and R 2are Nmethylpyrrol-2-yl and N-methylpyrrol-3-yl.
Compounds of formula I are, for example: 00 00 0 0' N-(4-(N-methylpyrrol-2-.yl)-4-phenylbut-3-en-l-yl)nipecotic 0 0 acid, O 0 a N-(4-(N-methylpyrrol-2-yl)--4-phenylbut-3-en-l-yl)guvacine, 0 0 N-(4-(N-methylpyrrol-2-yl)-4-phenylbut-3-en-1-yl)-8ho0or0ie 0 00 0001D N-4(N-methylpyrrol-3-yl )-4-phenylbut-3--en-l-yl)nipecotic acid, 0 at N- (4-(-etyprrl- y14-hn bt-3-n y1)gvcie 0 20 N-(4-(furan-2--yl)-4-phenylbut-3-en-l-'yl)nipecotic acid, N- (furan-2-yl )-4-phenylbut-3-en-l-yl )guvacine, N-(4-(furan-2-yl)-4-phenylbut-3-en--l-yl)-O-homoproline, N-(4-(furan-3-yl)-4-phenylbut-3-el-l-yl)fipecotic acid, N-.(4-(furan-3-yl)-4-phenylbut-3--en-1-yl)guvacine, N-(4-(furan-3-yl)-4-phenylbut-3-en-1-yl)- -homoproline, N-(4-phenyl4-(pyridin-2-yl)but-3-en-1yl)lipecotic acid, N- (4-phenyl-4- (pyridin-2-yl )but-3-en-l-yl )guvacine, N-(4-phefyl-4-(pyridin-3-yl)but-3-efl-l-yl)nipecotic acid, N-(4-phenyl4-(pyridin-3yl)but3e'1-Y1)uvacie, N- (4-phenyl -4 -(pyridi.f-3 -yl but- 3-en- I-yl -6-homoprol ine, N-(4-phenYl-4-(pyridin-4-Yl)but-3-en--yl)liPecotic acid, N- (4-phenyl -4 -(pyridin-4 -yl) but- 3-el-l-yl) quvacine, N-(4-phenyl-4-(pyridin-4-yl)but-3-en-l -homoprlile, N -(4-phenyl-4-(pyrazin-2-yI)but-3-efl-1-yl)nipecotic acid, 4 TcN/VMN, 1986-12-16, 30, D-363, IL 3020,200 N- (4-phenyl-4- (pyrazin-2-y. )but-3-en-1-yl )guvaciner N- (4-phenyl-4- (pyrazin-2-yl )but-3-en-1-yl) -homoproline, N-(4-phenyl-4-(pyrazin-3-yl)but-3-en-1-yl)nipecotic ac.1.d, N-(4-phenyl-4-(pyrazin-3-yl)but-3-en-1-yl)guvac-ine, N-(4-phenyl-4-(pyrazin-3-y)but-3-en-1-y)--honoproline, N-(4-(l-rnethylimidazol-2-yl)-4-phenylbut-3-en-1-yl)nipecotic acid, N-(4-(l-methylimidazol-2-yl)-4-phenylbut-3-en-1-yl)guvacine, N- (4-(l-Iethylimidazol-2-yl)-4-phenylbut-3-en-1-yl)-Bhomoproline, 00 00 N-(4-(l-methylimidazol 4-y1)-4-phenylbut-3-en-1-y1)nipecotic 0O O 0 acid, -0 N-(4-(1-methylimidazol-4-yl)-4-phenylbut-3-en-1-yl)guvacine, 0015 honoproline, 1101o00 N-(4-(l-ntethylimidazol-5-yl)-4-phenylbut-3-en-1-yl)nipecotic 00000 acid, N-(4-(1-methylimidazol-5-y)-4-phenylbut-3-el-1-y)guvacifle, 0 N-(4-(l-methylimidazol-5-yi)-4-phenylbut-3-en-1-yl)-goi} ,20 homoproline, 0 N-(4-(2-methylphenyl)-4-(N-mfethylpyrrol-2-yl)but-3-elyl)nipecotic acid, N-(4-(2-methylphenyl)-4-(N-methylpyrrol-2-yl)btit-3-elyl)guvacifle, N-(4-(2-methylpheny)-4-(N-methylpyrrol-2-yl)but-3-en-1-yl)- hornopro line, N-(4-(2-methylphenyl)-4(Nfethylpyrrol-2-y1)but-3-efly1)nipecotic acid, N-(4-(2-nethylpheflyl)-4-(N-methylpyrrol>3yl)but-3-efl'>yl)guvacine, N-(4-(2-methylphenyl)-4-(N-methylpyrrol-3-yl)but-3-en-1-yl)-5hornopro line, N-(4-(2-methylphenyl)-4-(pyridiri-3-yl)but-2-en-1-yl)nipecotic acid, N-(4-(2-methylphenyl)-4-(pyridiin-3-y)l)but-2-en-1-yl)guvacine, ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 N- (2-methyiphenyl) (pyridin-3-yl )but-2-en-1-yl) hornoproline, N- (2-methyiphenyl) (pyridin-3-yl )but-3-en-l-yl )nipecotic acid, N-(4-(2-methylphenyl)-4-(pyridin-3-yl)but-3-en-l-yl)guvacine, N(-2-methylphenyl)-4-(pyridin-3-yl)but-3-en-1-yl)-ghomopro line, N-(4-(N-rnethylpyrazol-3-yl)-4-phenylbut-3-en-1-yl)nipecotic acid, N-(4-(N-methylpyrazol-3-yl)-4-phenylbut-3-en-l-yl)guvacine, N-(4-(N-methylpyrazol-3-yl)-4-phenylbut-3-en-1-yl)-a- 0 homoproline, of N-methylpyrazol-4-yl)--4-phenylbut-3-en-l-yl)nipecotic 000000 acid, 0 0 00 15 N-(4-(N-rnethylpyrazol-4-yl)-4-phenylbut-3-en-l-yl)guvacine, o00 0 oN- (4-N-nethylpyrazol-4-yl -4-phenylbut-3-en-1-yl) 00000 homoproline, N- (N-methylpyrazol-S-yl) -4-phenylbut-3-en-1-yl )nipecotic 0n 0 0 acid, 0 004 0420 N-(4-(N-methylpyrazol-5-y1)-4-pheflb~ut->en-1-yl)guvacile, 0Of N-(4-(N-methy ,pyrazol15y)-4-phenlbut-3-efl-1-yl)- 000%homoproliie, 0 N-(4-(2-methylphelyl)-4-(N-mtethylpyrazol-3-yl)but-3-elyl )nipecotic acid, 0" 25 N-(4-(2-rnethylphefyl)-4-(N-methylpyrazol-3-y1)but-3-elyl )guvacine, N-(4-(2-tnethylphefyl)-4-(N-methylpyrazol-3-yl)but-3-efl-l-y1)- $-homoproline, N- (2-methyiphenyl) (N-nethylpyrazol-4-yl )but-3-en-lyl)nipecotic acid, N- (2-methyiphenyl )-4-(N-methylpyrazol-4-yl)but-3-en-1yl )guvacile, N-(4-(2-Inethylphefyl)-4-(N-methylpyrazol-4-yl)but-3-en-1-yl)- 0-homoproline, N-(4-(2-xnethylpbenyl)-4- (N-Inethylpyrazol-5-yl)but-3-nyJ.) nipecotic acid, 6 ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 -methylphenyl)-4-( N-methylpyrazol-5 -yl)but- 3 en-lyl)guvacine, N-(4-(2-methylphenyl)-4-(N-methylpyrazol-5-y1)but-3-en-1-yl)a-homoproline,
N-(
4 2 -methylphenyl)-4-(-methylimidazol-2-yl)but-3-en-lyl)nipecotic acid,
N-(
4 2 -methylphenyl)-4-(l-methylimidazol-2-yl)but-3-en-lyl)guvacine, N- (4-(2-methylphenyl)-4- (l-methylimidazol-2-yl)but-3-en-1-yl) a-homoproline
N-(
4 3 -methyl-2-thienyl)-4-pheny1but-3-en-1-yl)nipecotic acid, 00 00 o N-( 4 -(3-methyl-2-th ienyl)-4-phenybut-3-en-1-yl)guvacine, oo0 N-( 4 -(3-methyl-2-thienyl)-4-phenylbut-3-en-l-yl)homoproline ooooo and salts thereof.
0 0 0o 15 Compounds of formula I may exist as geometric and o O optical isomers and all isomers and mixtures thereof are 0 00 00 0 0ooo included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional 00 crystallisation.
0 t 0 20 Cne embodiment of this invention is non-toxic o C pharmaceutically acceptable salts of compounds of formula I.
Salts include those derived from inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, maleic and phthalic acid.
Compounds of formula I may be prepared by Nalkylation of a compound of the general formula II H-R'3 (I) wherein R'3 has the same mraning as R 3 with the proviso that the carboxy group is protected, for example, by an ester group, with a compound of the general formula III 7 ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 1 R -C=CH-CH 2
-CH
2
X
S(III)
2 1 2 wherein R and R are as defined in Claim 1, and X represents halogen. This reaction may be carried out in an inert solvent in the presence of an alkali metal carbonate, for example, potassium carbonate at, for example, room temperature, for from about 1 to 12 dys. The solvent may conveniently be acetone or N,N-dimethylformamide. Compounds of formula I may be prepared S 10 by hydrolysis of the resulting ester, preferably at room temperature in a mixture of an aqueous sodium hydroxide S°o, solution and an alcohol such as methanol or ethanol for from 0 oo.,o about 0.5 to 4 hours.
o o S oo Compounds of formula III may be prepared by reacting 0 000 0 oo 15 the appropriate disubstituted ketones with a Grignard reagent, i .o 00 cyclopropyl magnesium bromide, followed by ring opening of the intermediate cyclopropyl carbinol derivative by 0 treatment with hydrogen bromide in acetic acid. Alternative 0 00g o oe conditions involve the use of trimethylsilyl chlor.de and 0 Q0 lithium iodide in, for example, dichloromethane.
Sooao. Compounds of formula I are useful because they 0 possess pharmacological activity in man. In particular, the compounds of formula I are useful as inhibitors of GABA uptake.
0 For the above indications, the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about mg to about 2 g of compounds of formula I, conveniently given from 1 to 5 times daily, optionally in sustained release form. Usually, dosage forms suitable for oral administration comprise from about 25 mg to about 1 g of the compounds of formula I admixed with a pharmaceutical carrier or diluent. No toxic effects have been observed at these levels.
8 7 8 ToN/VMN, 1986-12-16, 30, D-363, IL 3020.200 The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit approximately the same order of activity as the free base forms.
This invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The compositions of this invention may be prepared by conventional techniques to appear in conventional forms, for example, capsules or tablets.
a The pharmaceutical carrier employed may be conventional solid or liquid carriers. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, oo .C acacia, magnesium stearate and stearic acid. Examples of liquid 15 carriers are syrup, peanut oil, olive oil and water. Similarly, go the carrier or diluent may include any time delay material well Oo known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
If a solid carrier for oral administration is used, oO, 20 the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or ar. lozenge. The amount of solid carrier will vary widely but, usually, will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may appear in the form of a S 25 syrup, emulsion, soft gelatin capsule or st-"ile injectable liquid such as an aqueous or non-aqueous liquid suspension.
The pharmaceutical compositions of this invention can be made following the conventional techniques of the pharmaceutical industry involving mixing, granulating and compressing or variously mixing and dissolving the ingredients as appropriate to give the desired and product.
The route of administration may be any route which effectively transports the active compound to the appropriate or desired place, such as orally or parenterally, the oral route being preferred.
A
ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 The features disclosed in the foregoing description and in the following examples and claims may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.
The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which, however are not to be construed as limiting. The examples illustrate some preferred embodiments.
Hereinafter T.l.c. is thin layer chromatography, THE is tetrahydrofuran and EtOH is ethanol.
o0 a Example 1 O2 o oo Cyclopropyl-(N-methylpyrrol-2-yl)phenylmethanol o a 9'00 *To a suspension of magnesium turnings (5,29 g, 0.22 molel in anhydrous tetrahydrofuran (70 ml), cyclopropyl bromide (26.35 g, 0.22 mole) in tetrahydrofuran (50 ml) was added dropwise under nitro-gn. The reaction mixture was heated at o" oreflux for one hoj, after the initial exotherm had subsided before N-methylpyrrol-2-ylphenylketone (13.3 g, 0.072 mole) (J.White and G. McGillivray, J.Org.Chem., (1977), 42, 4248, R.
Greenhouse and C. Ramirez, J.Org.Chem., (1985), 50, 2961) in anhydrous tetrahydrofuran (50 ml) was introduced dropwise.
After heating the reaction mixture at reflux for 3 hours it was cooled and saturated, aqueous ammonium chloride solution ml) and water (150 ml) were added. The mixture was extracted with ethyl acetate (3 x 200 ml) and the combined extracts were dried (MgSO4). Flash chromatography of the residue on evaporation on silica gel eluting with heptane/tetrahydrofuran provided the title compound as an oil (9.9 g, 46%) which solidified on standing. T.l.c. rf 0.35 (SiO 2 heptane/THF I, I TON/VMN, 1986-12-16, 3o, D-363, IL 3020.200 Ring opening of cyclopropylcarbinol: Method A Bromo-4-(N-methylpyrrol-2-yl)-4-phenylbut-3-ene Cyclopropyl-(N-methylpyrrol-2-yl)phenylmethanol was dissolved in acetic acid (60 ml) and a mixture of acetic acid (30 ml) and 48% hydrobromic acid (15 mi was added at 5 0 C. The mixture was stirred for 30 minutes and poured into water (300 ml). The resultant emulsion was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with saturated sodium bicarbonate solution and brine and dried (Na 2
SO
4 The concentrate, containing some acetic acid, was passed through a silica column (Merck Art 9385) with heptane/tetrahydrofuran (19:1) as eluent. After further flash chromatography in the same solvent system, the pure bromide (Z 00 0 o0 0 isomer) was obtained. T.l.c. rf 0.35 (Sio 2 heptane/THF o00oal5 00 0 0 000000 0 0 00 0 0 0 Method B Balmo, G. Fournet and J. Gore, Tetrahedron. Lett., 0 04 t: (1905), 1907 4-(N-Methylpyrrol-2-yl )-4-phenylbut-3-en-1-yl chloride and a iodide Cyclopropyl-(N-methylpyrrol-2-yl )phenyliethanol (6.46 g, 28.4 mmol) was dissolved in dichloromethane (200 ml) and lithium iodide (4.56 g, 31.4 mmol) was introduced. The mixture was cooled to 0 0 C, and chlorotrimethylsilane (3.6 ml# 28.4 mmol) was a:ied dropwise. After 2 hours at OOC, the reaction mixture was filtered and evaporated to a dark green oil (7.28 lash chromatoqgraphy on sil.ica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran (19:1) provided the title compounds as an oil (6.3 g, 646) (a mixture of E and z isomers). T.I.c. rf t 0.29 (SiO 2 heptane/THPF ToN/VMN, 1986-12 1A. 3o, D-363, IL 3020 .200 (N-Methvlpyrrol-2-yl) -4-phenylbut-3-en-l-yl nipecotic acid ethyl ester 4- (N-Methylpyrrol-2-yl )-4-phenylbut-3-en-1-yl chloride and iodide (3.0 g, 8.7 minol)- were dissolved in anhydrous acetone (50 ml) and dried potassium ca-bonate (4.8 g, 34.8 mmol), sodium iodide (1.3 g, 8.7 mmol) and the Renantiomer of ethyl nipecotate (1,462 g, 9.3 rnmol) (A.M.
Akkerrnan et al., Rec.. Trav. Chem., 1951, 70, 899; G. Bettoni et al., Gazz. Chem. Ital. 1972, 102, 189) was added. The suspension was stirred at zoomn temperature for 10 days, r-'ltered and evaporated to a gummy residue which was puritied by flash chromatography on silica gel (Merck Art 9385). Elution with heptane/tetrahydrofuran (19:1) provided the title ester (1.74 0 0) 0" g, 54%) as an oil, TA c. rf 0.06 (SiQ hepte'ne/THF 0 0 00 0 o:0015 R-N- (4 -(N-Methylpyrro ,2 -y 1-4 -pheny lbut- 3-en 1-yl nipe cot ic 0 00 t acid hydrochloride (NO-05-0356) 0 a04 R -N i4- (N-Methylpyrro 1- 2-y1) -4 -pheny lbut 3-en ,l)nipecotic acid ethyl ester (1.74 g, 4.7 mmol) was dissolved 009 0 in ethanol (50 ml) and 10 N sodium hydroxide solution (8.9 ml) 0 20 was added. The solution was stirred at room temperature for miutes an'. cooled to 0 0 C. The pH was adjusted to 5 with 4 N hydrochloric acid solution, and the solution was extracted wtith dichlorome~hane (4 x 25 ml). The combined extracts were washed with water 110 ml) and dried (MgSO 4 The residue on evaporation was treated with water (100 ml) and activated charcoal. Filtration through a millipore filter gave a solution which was frezedried to give tche product as az cream solid (1,53 g, It was found that the E and Z isomers could be separated by kIPIC.
ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 Example 2 N-(4-(N-Methylpyrrol-2-yl)-4-phenylbut-3-en-l-yl)nipecotic acid ethyl ester l-Bromo-4-(N-methylpyrrol-2-yl)-4-phenylbut-3-ene (4.58 g, 15.9 mmol) was dissolved in anhydrous acetone (115 ml) and dried potassium carbonate (8.78 g, 63.6 mmol) was introduced, followed by ethyl nipecotate (3.25 g, 20.7 mmol).
The reaction mixture was stirred at room temperature for 12 days, filtered and evaporated to give a brown oil (6.4 g), Column chromatography on silica gel (Merck Art 15111) eluting with heptane/tetrahydrofuran (19:1) provided the title compound as an oil (3.68 g, T.l.c. rf 0.31 (SiO 2 THF neptane 0 0 O o 0 00 0 o0ooo0 5 N-(4-N-Methylpyrrol-2-yl)-4-phenylbut-3-en-l-yl)nipecotic acid 0 hydrochloride (NO-05-0165) 0 0 0a o oI e N-(4-(N-Methylpyrrol-2-yl)-4-phenylbut-3-en-lyl)nipecotic acid ethyl ester (2.75 g, 7.5 aimol) was dissolved i o, in ethanol (70 ml). 10 N sodium hydroxide solution (14 ml) was I 20 introduced, and the solution was stirred for 30 minutes at room temperature before being cooled to 0°C. The pH was adjusted to 7 with 4 N hydrochloric acid solution, and the reaction mixture was extracted with dichlcromethane (4 x 100 ml) (emulsion). The combined organic extracts were washed with a mixture of saturated brine (20 ml) and water (20 ml). The layers were separated, and the aqueous phase was washed with dichloromethane (100 ml). The combined extracts were dried (Na 2
SO
4 and filtred through "hyflo". The filtrate was evaporated and the residue dissolved in 150 ml water, decolourised (charcoal) and freeze dried. The title amino acid was obtained as a dense white powder (Z isomer) (1.83 g, 72%).
T.l.c. rf 0.33 (SiO 2 dichloromethane/methanol r 13 ToN/VMN, 1986-12-16, 30, D-363, IL 3020.200 Example 3 2-Benzoyl-N-ethylpyrrole 2-Benzoylpyrrole (ref. as in Example 1) (10.27 g, 0.06 mole) was dissolved in dry N,N-dimethylformamide (120 ml) and combined with sodium hydride (2.016 g, 0.084 mole) (60% oil dispersion) in dry N,N-dimethylformamide (120 ml). The re&ation mixture was stirred at room temperature for 18 hours and water (100 ml) was added. The reaction mixture was extracted with diethyl ether (3 x 100 ml) and the combined extracts were washed with water (200 ml). The organic layer was dried (MgSO 4 g oo0 and evaporated to give the title compound as an oil (11.74 g, o 0 ooo T.1.c. rf 0.53 (SiO 2 dichloromethane/methanol 0o This ketone was converted into a mixture of 4-(N- 0 S15 ethylpyrrol-2-yl)-4-phenylbut-3-en-l-yl chloride and iodide by Oo 0 °oR the method described in Example 1 (using Method B) o Oa 0 0 R-N-((4-N-Ethylpyrr-l-2-yl)-4-pheylbut-3-en-l-yl)nipecotic acid ethyl ester 4-(N-Ethylpyrrol-2-yl)-4-phenylbut-3-en-l-yl chloride and iodide (3.16 g, 9 mmol) were dissolved in anhydrous acetone ml) and dried potassium carbonate (4.97 g, 36 mmol), sodium iodide (2.7 g, 18 mnmol) and the R-enantiomer of ethyl nipecotate (1.93 g, 13.7 mmol) were introduced. The suspension was stirred at room temperature for 10 days, filtered and evaporated to a residue. The residue was purified by column chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran providing the title ester (1.50 g, 43%) as a gum. T.l.c. rf 0.21 (Si02, heptane/THF 14 ToN/VMN, 1986-12-1 6 30, D-363, IL 3020.200 4 -NEthylpyrrol-2-yl)-4-phenylbut-3-en-1-yl)nipecotic acid 4 -N-Ethylpyrrol-2-yl)-4-phenylbut-3-en-lyl)nipecotic acid ethyl ester (0.14 g, 0.4 mmol) was hydrolysed by the method outlined in Example 1. The title acid was obtained as a freeze-dried solid (Z isomer) (54 mg, m.p.
56.5 60 0 C (decomposition).
Example 4
N-(
4 -(N-Methylpyrrol-2-yl)-4-phenylbut-3-en-1-yl)guvacine methyl ester 0 0 co. 4- (N-Methylpyrrol-2-yl) -4 -phenylbut-3-en-l-yl Co 0 chloride and iodide (1.46 g, 4.3 mmol) (Example 1) were dissolved in anhydrous acetone (30 ml) and dried potassium o, carbonate (2.37 g, 17.2 mmol), sodium iodide (0.645 g, 4.3 o 15 mmol) and guvacine methyl ester hydrochloride. (0.995 g, 5.6 mmol) were added. The suspension was stirred at room temperature for 5 days, and worked up as described in Example 1 to give the title ester (1.1 g, 72%) as a fawn oil (mixture of E and Z isomers). T.l.c. rf 0.05 (Si02, heptane/THF N-(4-(N-Methylpyrrol-2-yl)-4-phenylbut-3-en-1-yl)guvacine hydrochloride (mixture of E and Z isomers) (NO-05-0387) N-(4-(N-(Methylpyrrol-2-yl)-4-phenylbut-3-en-lyl)guvacine (1.02 g, 2.9 mmol) was hydrolysed by the method outlined in Example 1. The title acid was obtained as a freeze dri6 solid (0.64 g, melting point: 81.5 84 0 C (E and Z isomers).
f, t ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 N-(4-(N-Methylpyrrol-2-yl) -4-phenylbut-3-en-1-yl) guvacine methyl ester l-Bromo-4-(N-methylpyrrol-2-yl)-4-phenylbut-3-ene (0.60 g, 2.08 mmol) was dissolved in anhydrous acetone (20 ml) and dried potassium carbonate (1.10 g, 8 mmol) was introduced, followed by guvacine methyl ester hydrochloride (0.37 g, 2.08 mmol). The reaction mixture was stirred at room temperature for days and worked up as described in Example 1 to give the title ester (Z isomer) (380 mg, 52%) as an oil. T.l.c. rf 0.32 (Si02, heptane/THF N-(4-(N-Methylpyrrol-2-yl) -4-phenylbut-3-en-1-yl)guvacine hydrochloride (Z-isomer) N0-05-0227 0 i 0 N-(4-(N-Methylpyrrol-2-yl)-4-phenylbut-3-en-l- 0,o 06 0 a yl)guvacine methyl ester was hydrolysed by the method outlined 0 O'0 15 in Example 1. The title acid was obtained as a freeze dried on, white powder (60 mg, melting point: 70 0
C.
0 Example Cc clopropylphenyl- (4 -pyridyl) methanol Magnesium turnings (2.65 g, 0.109 mole) in dry tetrahydrofuran (50 ml) was treated dropwise with cyclopropyl bromide (13.2 ml, 0.109 mole). The reaction mixture was heated at reflux for 1 hour after the initial exotherm had subsided, and then 4-benzoylpyridine (10 g, 0.0545 mole) was introduced.
Heating at reflux was continued for 2 hours, the reaction mixture was cooled,and saturated ammonium chloride solution ml) was added. This aqueous phase was extracted with ethyl acetate (3 x 200 ml) and the combined extracts were dried (MgS04). Evaporation gave a crude solid residue (6.23 g) which 16 ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 was recrystallized from toluene to give the title alcohol (2.57 g, m.p. 171 172 0 C. T.l.c. rf 0.065 (SiO 2 THF/heptane l-Bromo-4-phenyl-4-(4-pyridyl)but-3-ene Cyclopropylphenyl-4-(4-pyridyl)methanol (2.4 g, 10.6 mmol) was dissolved in acetic acid (25 ml). The solution was cooled to o0C. A 47% solution of hydrogen bromide (5 ml) was added and the reaction mixture was stirred at room temperature for 3.5 hours, and at 40 0 C for 1 hour. The reaction mixture was poured into water (100 ml) and this aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts B on were washed with saturated sodium bicarbonate solution (40 ml) and saturated brine (40 ml) and dried (MgSO Evaporation gave "o0 a crude product (3.26 g) which was purified by flash a 15 chromatography on silica gel (Merck Art 9385). Elution with 0" heptane/ethyl acetate provided an oil (1.38 g, 45%) which solidified on standing. T.l.c. rf 0.13 (SiO 2 heptane/ethyl acetate N-(4-Phenyl-4-(4-pyridyl)but-3-en-l-yl)nipecotic acid, ethyl ester l-Bromo-4-phenyl-4-(4-pyridyl)but-3-ene (1.0 g, mmol), ethyl nipecotate 2 g, 4.6 mmol) and potassium carbonate (1.93 g, 14.0 nmlol) were stirred at room temperature for 5 days. The reaction mixture was filtered, and evaporated to a residue which was purified by flash chromatography on silica gel (Merck Art 9385). Elution with dichloromethane/ethanol/ 25 ammonium solution (190:9:1) provided the title compound as an oil. T.l.c. rf 0.23 (SiO 2
CH
2 C12/EtOH/NH 3 (190:9:1)).
e- 17 ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 N-(4-Phenyl-4-(4-pyridyl)but-3-en-l-yl)nipecotic acid hydrochloride (N0-05-0358 N-(4-Phenyl-4-(4-pyridyl)but-3-en-l-yl)nipecotic acid ethyl ester was hydrolysed by the method outlined in Example 1.
The title acid was obtained as a freeze dried solid.
Example 6 Co oo 2-Methylphenyl-4-pyridylmethanol O 0 0000 Magnesium turnings (3.2 g, 0.131 mole) in dry 00o" tetrahydrofuran (50 ml) were treated dropwise with 2o o 10 bromotoluene (15 g, 0.087 mole). The reaction mixture was Qo oo o°00° heated at reflux for I hour after the initial reflux had 0000 subsided. After cooling, 4-pyridylcarboxaldehyde (14.38 g, 0,131 mole) in dry tetrahydrofuran (30 ml) was introduced 00 0oo, slowly, aind subsequently the reaction mixture was heated at o o" 15 reflux tor 2 hours. The reaction was worked up as in Example 0 O (Grignard reaction) to give the title alcohol (5.92 g, 34%).
0'0* T.l.c. rf 0.24 (SiO 2 ethyl acetate).
oI 4-(2-Methylbenzoyl)pyridine Pyridinium chlorochromate (9.29 g, 43.1 mmol) was dissolved in dichloromethane (50 ml) and a solution of 2methylphenyl-4-pyridylmethanol (5.72 g, 28.7 mmol) in dichloromethane (30 ml) was added. The reaction mixture became dark immediately, and was stirred for 2 hours at room temperature. Diethyl ether (350 ml) was added, and the reaction mixture was filtered through "hyflo" and evaporated to a dark oil (11.26 Flash chromatography on silica gel 'Merck Art I. I 18 ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 9385) eluting with heptane/tetrahydrofuran provided the title compound (2.74 g, 48%) as an oil. T.l.c. rf 0.45 (SiO2' ethyl acetate).
This ketone was converted into l-bromo-4-(2methylphenyl)-4-(4-pyridyl)but-3-ene by the method described in Example 1 (Method A).
N-(4-(2-Methylphenyl)-4-(4-pyridyl)but-3-en-l-yl)nipecotic acid ethyl ester 00 0J, o0 o 0 0 l-Bromo-4-(2-methylphenyl)-4-(4-pyridyl)but-3-ene o J 10 (1.9 g, 7.6 mmol) was dissolved in anhydrous acetone (30 ml) and dried potassium carbonate (4.2 g, 30.4 mmol) and ethyl ooo mipecotate (2.39 g, 15.2 mmol) were introduced. The suspension o° was stirred at room temperature for 18 hours, filtered and oooo evaporated to a residue. The residue was purified by "flash" chromatography on silica gel (Merck Art 9385) eluting with 0ooo heptane/tetrahydrofuran to provide the title ester (0.67 oo g, 41%) as a reddish oil (a mixture of E and Z isomers). T.l.c.
0 0 rf 0.08 (Si02; heptane/THF N-(4-(2-Methylphenyl)-4-(4-pyridyl)but-3-en-1-yl)nipecotic acid N-(4-(2-Methylphenyl)-4-(4-pyridyl)but-3-en-lyl)nipecotic acid ethyl ester (0.67 g, 1.8 mmol) was dissolved in ethanol (20 ml) and 10 N sodium hydroxide solution (3.42 ml) was added. The solution was stirred at room temperature for Shours, and the pH was adjusted to 5 with 4 N hydrochloric acid.
The solution was applied to a column of Dowex 50WX8 ion exchange resin (H form). Elution with water followed by dilute ammonia solution provided the title acid (180 mg, fL .Itrtt 19 TON/VMN, 1986-12-16, 30, D-363, IL 3020.200 Example 7 2-Methylphenyl-(3-methyl-2-thienyl)methanol The title compound was prepared from 2-bromotoluene (35.55 g, 0.208 mole), magnesium turnings (5.1 g, 0.208 mole) and 3-methylthiophene-2-aldehyde (23.6 g, 0.187 mole) by the method described in Example 6, using diethyl ether (150 ml) as solvent. The yield was 36.0 g T.l.c. rf 0.39 (Sio 2 heptane/THF D0 00 00
OO
0 0000 0 0 0 1 3-Methyl-2-(2-methylbenzoyl)thiophene 0 000 00 0 0 00 Soo 10 2-Methylphenyl-(3-methyl-2-thienyl)methanol (36.0 g, 0 a 0.165 mole) was dissolved in dichloromethane (400 ml) and 0 "0 0o manganese dioxide (58 g, 0.667 mole) was added. The reaction mixture was heated at reflax for 18 hours, cooled and further 00 S"oo0 manganese dioxide (30 g, 0.34 mole) was introduced; reflux was 0o0 15 continued for a further 18 hours. The mixture was filtred and 0 00 evaporated to a residue (32 g) which was distilled in vacuo P (0.2 mm Hg). Fractions boiling at 100 120 0 C (4.8 g) and 120 132 0 C (21.0 g) were collected, giving the title compound as an oil (25.8 g, 72%).
The ketone was converted unto 1-bromo-4-(2methylphenyl)-4-(3-methyl-2-thienyl)but-3-ene by the method described in Example 1 (Method A) R-N-(4-12-Methylphenyl)-4-(3-methyl-2-ttienyl)but-3-en-lyl)nipecotic acid ethyl ester 1-Bromo-4- (2-methylphenyl)-4-(3-methyl-2thiinyl)but-3-ene (3.0 go 9.34 mmol) was dissolved in anhydrous acetone (40 ml) and dried potassium carbonate (1.38 g, 10 mmol) potassium iodide (0.2 g, 1 mmol) and the R-enantiomer of ethyl 1_1_1_ ToN/VMN, 1986-12-16, 30, D-363, IL 3020.200 nipecotate (1.57 g, 10 mmol' were introduced. The suspension was stirred at room temperature for 18 hours, filtered, and evaporated to a residue. The residue was purified by "flash" chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran to provide tne title ester (2.4 g, 65%) as an oil. T.l.c. rf 0.40 (SiO 2 heptane/THF R-N-(4-(2-Methylphenyl)-4-(3-methyl-2-thienyl)but-3-en-lyl)nipecotic acid (NO-05-0340) 00 00 o 0 0 R-N-(4-(Z-Methylphenyl)-4-(3-methyl-2-thienyl)but-3- 000 oo 10 en-l-yl)nipecotic acid ethyl ester (1.4 g, 3.52 mmol) was "oo° hydrolysed by the method outlined in Example 1. The title acid Swas obtained as a solid (1.1 g, melting point: 65 67 0
C.
000o S0 9 Example 8 00 0 4 0 Cyclopropyl-2-furylphenylmethanol S 15 To a suspension of magnesium turnings (0.26 g, 10.5 mmol) in anhydrous tetrahydrofuran (6 ml) cyclopropyl bromide (1.28 g, 10.5 mmol) in tetrahydrofuran (5 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for 1 hour after the initial exotherm had subsided before 2-benzoylfuran (12 g, 7.0 mmol) was added as a solution in tetrahydrofuran (10 ml). The reaction mixture was worked up as described in Example 1 to give the title alcohol as an oi.
T.l.c. rf 0.23 (SiO 2 heptane/THF This compound was converted directly into l-bromo-4- (2-furanyl)-4-phenylbut-3-ene by the method described in Example 1 (Method A).
cT 1 II.
I-
ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 2 -Furanyl)-4-phenylbut-3-en-l-yl)nipecotic acid ethyl ester l-Bromo-4-(2-furanyl)-4-phenylbut-3-ene (0.23 g, 0.83 mmol) was dissolved in anhydrous acetone (10 ml) and dried potassium carbonate (0.46 g, 3.32 mmol) was added, followed by ethyl nipecotate (0.16 g, 1 mmol). The suspension was stirred at room temper.ture for 9 days, filtered and evaporated to a *residue. The residue was purified by column chromatography on silica gel (Merch Art 9385), eluting with heptane/tetrahydro- .0 furan to provide the title ester (140 mg, 47%) as an oil. T.l.c. rf 0.36 (SiO 2 heptane/THF N-(4-(2-Furanyl)-4-phenylbut-3-ene-l-yl)nipecotic acid N-(4-(2-Furanyl)-4-phenylb'it-3-en-l-yl)nipecotic acid ethyl ester (130 mg, 0.36 mmol) was hydrolysed by the method .5 described in Example 1. The title acid was obtained as a freeze dried solid. T.l.c. rf 0.43 (Sio,, methanol).
0 0 3 J 0 o a 3 3 0 0100o 00 0 a 0 0 Example 9 Preparation of Capsules.
Ingredients N-(4-(N-methylpyrrol-2yl)-4-phenylbut-3-en-l-yl)nipecotic acid Magnesium stearate Lactose Mg per Capsule 125 2 200 The above ingredients are thoroughly mixed and placed into hard gelatin capsules. Such capsules are administered orally to subjects in need of treatment from 1 5 times daily to enhance GABA'ergic activity in the central nervous system.
ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 Example Preparation of Tablets.
Ingredients Mg per Tablet N-(4-(N-methylpyrrol-2yl)-4-phenylbut-3-en-l-yl)nipecotic acid 200 Corn starch 46 Polyvinyl pyrrolidone 12 Magnesium stearate 1 The compound is thorougaiy mixed with two thirds of the corn starch and granulated. The granules obtained are dried, mixed with the remaining ingredients and compressed into tablets.
The capsules or tablets thus prepared are administered orally. Similarly, other compounds of formula I can be used.
00 0 0 0 0 10 S0 0 a 0 O 0 0I00 0 0 0 00 0 0 0 0ow PHARMACOLOGICAL T3ST introduction The convulsions induced by loud noise in the DBA/2 strain of mice is regarded as a reliable model fnr evaluating antiepileptic drug effects, cf. E.N. Petersen et al.: psychopharmacol, 83 (1984), 240, and A.G. Chapman et al.: Arzmeim.-Forsch. 10 (1984), 1261. The Rotarod and Traction tests were used to evaluate the sedative properties of the test drugs.
Methods Male DBA/2 mice (8 1 g) were used in all experiments. The animals were pretrained on the Rotarod (6 rpm; rod diameter 2.5 cm) for 1 minute. The compoinds tested were injected intraperitoneally. Twenty-five minutes later, the 23 ToN/VMN, 1986-12-16, 3o, D-363, IL 3020.200 animals underwent a 2 minutes' test on the Rotarod. The number of failures to stay on the rod was counted. An error rate higher than 10 was assigned the maximum score of Immediately after the Rotarod test, the animals were tested in a Traction test, cf. Psychopharmacol. above. In this test, the animal was required to maintain grasp on a thin rod (diameter mm) with the forepaws for five seconds and, within this period of time, to show a traction response (grasping onto the rod with one of the hindlcys). The performance on the test was based on the absence or presence of the traction response with the 5 seconds' test period. Finally, after the Traction test, o the animals were individually placed in a chamber in which they o were exposed for 30 seconds to a 14 kHz sinus tone at 111 dB.
on During this period of time, the following behaviors were noted: i 15 K.'ild running", clonic convulsions and death.
S 0 0 00 Drugs 0 The compounds tested were dissolved in distilled i o water or suspended in 5% chremophore. The injection volume was 0.2 ml/mouse.
0 Results obtained g* In table I, below, th- ratio ED 50 Rotarod/ED 50 tonic convulsions is given for the compounds tested. NO-05-0340 is R-N-(4-(2-methy' henyl)-4-(3-methyl-2-thienyl)but-3-en-lyl)nipecotic acid and NO-05-0356 is R-N-(4-(N-methylpyrrol-2yl)-4-phenylbut-3-en-1-yl)nipecotic acid.
1, 0 ToN/VMN, 1986-12-16, 30, D-363, IL 3020.200C Table I Comp~ound- NO-05-0340 -03 56 SK&F 1OU330A SK&F 89976A SK&F 100561 Ratio 0 0 0 0 0 0 0 0 0 0 0 0 00
Claims (17)
1. Phenylbuten derivatives of the general formula I R -C=CH-CH2-CH2-R 3 22 R wherein R 1 represents phenyl optionally substituted by one, two or more substituents selected from the group consisting of halogen, lower alkyl, and lower alk.xy, R2 represents pyrrolyl, furany', pvridinyl pyrazinyl, imidazolyl pyrazolyl, pyrimidinyl pyrrolldinyl, tetrahydrofuranyl, piperidinyl or piperazinyl each of which may be subs~ituted by one, two or more substituents selected from the group consisting of halogen, lower alkyl and lower alkoxy or R2 represents a thienyl group substituted by a loweralkyl group which substituted thienyl group may be further substituted by one, two or more substituents selected from the group consisting of halogen, lower alkyl, and lower alkoxy, and R represents
3-carboxypiperid-l-yl 3-carboxy-l,2,5,6-tetrahydropyrid--yl or 3-carboxymethylIpyrrolidin-l-yl, the corresponding amides or lower alkyl esters, or salts thereof. 2. Derivatives, according -to Claim 1, characterized in that R3 is 3-carboxypiperid-l-yl or 3-carboxy-1 2,5,6-tetrahydropyrld-l-yl, 3, Derivatives, according to Claim 1 or 2, characterized in that R 2 represents pyrrolyl, furanyl, pyridinyl, pyrazinyl, imilazolyl, pyrazolyl pyrimidinyl tetrahydrofuranyl piperidinyl or thienyl substituted by a lower alkyl group, each of which i y be substituted by one, two or more substituents selected from the group consisting of halogen, lower alkyl, and lower alkoxy.
4. Derivatives, according to any one of the preceding claims, wherein R2 is 2-pyrrolyl, Derivatives, according to any one of the Claims 1 through 3, wherein R 2 Is 2-furanyl.
6. DerivatIves, according to any one of the C'ialms 1 through 3, wherein R2 Is 2-imidazolyl.
7. DerivatIves, according to any one of the Claims 1 through 3, wherein R 2 is N-methylpyrazolyl.
8. Derivatives, according to any one of the Claims 1 through 3, wherein R2 is 5-pyrimidinyl.
11. 3-methylthi
12. characteriz methyl, eth
13. characteriz alkyl.
14. methyl, eth wherein R
16. stated in a carrier, di
17. r> contain fro >i o 18. patient, wh' said increa at least a composition
19. or a salt t formula IV wherein R converting z into a comp(
20. 1 herein descr
21. P described wI 22, a patient, 1 ,3WBSl Kk 8511U 26 11. Derivatives, according to Claim 9 or Claim 10, wherein R 2 is 3-methylthien-2-yl. 12. Derivatives, according to any one of the Claims 1 through 3, characterized in that R is phenyl substituted by chloro, bromo, fluoro, methyl, ethyl or methoxy. 13. Derivatives, according to any one of the Claims 1 through 3, characterized in that the heterocyclic group is substituted with lower alkyl. 14. Derivatives, according to Claim 13, wherein the lower alkyl is methyl, ethyl, isopropyl or propyl. Derivatives, according to any one of the Claims 1 through 3, wherein R 2 is N-methylpyrrol-2-yl. 16. Pharmaceutical compositions containing a compound of formula I stated in any one of the preceding claims or a salt thereof together with a oo carrier, diluent and/or excipient. 17. Compositions, according to Claim 16, characterized in that they contain from about 25 mg to about 1 g of the compound. o 18. A method for increasing GABA'ergic activity and/or sedating a o°u patient, which method comprises administering to said patient requiring I said increase in GABA'ergic activity and/or sedation an effective amount of at least a derivative according to any one of Claims 1 to 15 or a composition according to Claim 16 or Claim 17. 19. A process for preparing compounds of formula I stated in Claim 1 S or a salt thereof, characterized in hydrolysirg a compound of the general formula IV S. R 1 -C=CH-CH -CH R 13 (IV) S12 R wherein R 1 R 2 and R' 3 each are as defined above, and, if desired, converting a compound of formula I into a salt thereof or converting a salt into a compound of formula I. A N-(butenyl-substituted)azaheterocyclic carboxylic acid as herein described with reference to any one of Examples 1 to 8. 21. A pharmaceutical composition, substantially as hereinbefore described with reference to Example 9 or Example
22. A method for increasing the GABA'ergic activity and/or spating a patient, which method comprises administering to said patient requ. J 0/7 511U h M^y J t .r r *i ;r fs^E.-F- 27 said increase in GABA'ergic activity and/or sedation an effective amount of a derivative according to Claim 20 or a composition according to Claim 21.
23. A process for preparing a N-(butenyl-substituted)azaheterocyclic carboxylic acid, substantially as hereinbefore described with reference to any one of Examples 1 to 8. DATED this FOURTH day of MAY 1990 Novo Industri A/S Patent Attorneys for the Applicant SPRUSON FERGUSON
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK51/86 | 1986-01-07 | ||
| DK5186A DK5186D0 (en) | 1986-01-07 | 1986-01-07 | AMINO |
| DK95686A DK95686D0 (en) | 1986-03-03 | 1986-03-03 | |
| DK956/86 | 1986-03-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6719387A AU6719387A (en) | 1987-07-09 |
| AU600248B2 true AU600248B2 (en) | 1990-08-09 |
Family
ID=26063196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU67193/87A Ceased AU600248B2 (en) | 1986-01-07 | 1987-01-07 | N- (butenyl-substituted) azaheterocyclic carboxylic acids |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4931450A (en) |
| EP (1) | EP0231996B1 (en) |
| JP (1) | JPH0791289B2 (en) |
| AU (1) | AU600248B2 (en) |
| CA (1) | CA1297105C (en) |
| DE (1) | DE3787657T2 (en) |
| DK (1) | DK165692C (en) |
| ES (1) | ES2059360T3 (en) |
| FI (1) | FI89481C (en) |
| IL (1) | IL81179A (en) |
| NO (1) | NO170976C (en) |
| PT (1) | PT84064B (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK704488D0 (en) * | 1988-12-19 | 1988-12-19 | Novo Industri As | NEW N-SUBSTITUTED AZAHETEROCYCLIC CARBOXYLIC ACIDS |
| DK288385D0 (en) * | 1985-06-26 | 1985-06-26 | Novo Industri As | AMINO ACID DERIVATIVES |
| DK270488D0 (en) * | 1988-05-18 | 1988-05-18 | Novo Industri As | Hitherto unknown O-SUBSTITUTED KETOXIMES |
| DK588189D0 (en) * | 1989-11-22 | 1989-11-22 | Novo Nordisk As | NEW HETEROCYCLIC CARBOXYLIC ACIDS |
| US5112980A (en) * | 1989-12-27 | 1992-05-12 | Monsanto Company | Process of preparing substituted pyridine compounds |
| US5962449A (en) | 1995-04-07 | 1999-10-05 | Novo Nordisk A/S | Tricyclic compounds in treating hyperalgesic conditions and NIDDM |
| US6191165B1 (en) * | 1996-05-31 | 2001-02-20 | Allelix Neuroscience Inc. | Pharmaceutical for treatment of neurological and neuropsychiatric disorders |
| WO1997049403A1 (en) * | 1996-06-27 | 1997-12-31 | University College Dublin | Use of nipecotic acid or guvacine derivatives for the manufacture of a medicament for the treatment of postischemic neurodegenerative disorders |
| US6503926B2 (en) | 1998-09-04 | 2003-01-07 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US6288083B1 (en) | 1998-09-04 | 2001-09-11 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| DE19840611A1 (en) * | 1998-09-05 | 2000-03-09 | Klaus Wanner | GABA uptake inhibitors with pyrrolidine structure |
| HRP20030696A2 (en) | 2001-02-16 | 2005-04-30 | NPS Allelix Corp. Allelix Neuroscience | GlyT-1 INHIBITORS |
| US7355042B2 (en) * | 2001-10-16 | 2008-04-08 | Hypnion, Inc. | Treatment of CNS disorders using CNS target modulators |
| US7189757B2 (en) * | 2001-10-16 | 2007-03-13 | Hypnion, Inc. | Treatment of sleep disorders using CNS target modulators |
| WO2003032912A2 (en) * | 2001-10-16 | 2003-04-24 | Hypnion, Inc. | Treatment of cns disorders using cns target modulators |
| CN1382441A (en) * | 2002-05-21 | 2002-12-04 | 中国科学院上海生命科学研究院 | Application of gammalon transporter inhibitor in preparing analgesic |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4383999A (en) * | 1981-05-26 | 1983-05-17 | Smithkline Beckman Corporation | Inhibition of GABA uptake by N-substituted azaheterocyclic carboxylic acids and their esters |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU552050B2 (en) * | 1981-05-26 | 1986-05-22 | Smithkline Beckman Corporation | N-substituted azeheterocyclic carboxylic acids and their esters |
| US4681884A (en) * | 1983-09-01 | 1987-07-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Diazine-ethenylphenyl oxamic acids and esters and salts thereof |
-
1987
- 1987-01-06 DE DE87300064T patent/DE3787657T2/en not_active Expired - Fee Related
- 1987-01-06 PT PT84064A patent/PT84064B/en not_active IP Right Cessation
- 1987-01-06 ES ES87300064T patent/ES2059360T3/en not_active Expired - Lifetime
- 1987-01-06 DK DK003887A patent/DK165692C/en not_active IP Right Cessation
- 1987-01-06 NO NO870049A patent/NO170976C/en unknown
- 1987-01-06 IL IL81179A patent/IL81179A/en not_active IP Right Cessation
- 1987-01-06 EP EP87300064A patent/EP0231996B1/en not_active Expired - Lifetime
- 1987-01-07 FI FI870059A patent/FI89481C/en not_active IP Right Cessation
- 1987-01-07 AU AU67193/87A patent/AU600248B2/en not_active Ceased
- 1987-01-07 CA CA000526869A patent/CA1297105C/en not_active Expired - Lifetime
- 1987-01-07 JP JP62000621A patent/JPH0791289B2/en not_active Expired - Lifetime
-
1988
- 1988-10-17 US US07/259,235 patent/US4931450A/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4383999A (en) * | 1981-05-26 | 1983-05-17 | Smithkline Beckman Corporation | Inhibition of GABA uptake by N-substituted azaheterocyclic carboxylic acids and their esters |
Also Published As
| Publication number | Publication date |
|---|---|
| NO170976C (en) | 1993-01-06 |
| DK165692C (en) | 1993-11-08 |
| DK3887D0 (en) | 1987-01-06 |
| NO170976B (en) | 1992-09-28 |
| EP0231996B1 (en) | 1993-10-06 |
| FI89481B (en) | 1993-06-30 |
| FI870059L (en) | 1987-07-08 |
| JPH0791289B2 (en) | 1995-10-04 |
| FI870059A0 (en) | 1987-01-07 |
| EP0231996A2 (en) | 1987-08-12 |
| PT84064B (en) | 1989-07-31 |
| DK3887A (en) | 1987-09-17 |
| DE3787657D1 (en) | 1993-11-11 |
| IL81179A (en) | 1992-02-16 |
| PT84064A (en) | 1987-02-01 |
| FI89481C (en) | 1993-10-11 |
| NO870049D0 (en) | 1987-01-06 |
| DE3787657T2 (en) | 1994-02-03 |
| US4931450A (en) | 1990-06-05 |
| JPS62228073A (en) | 1987-10-06 |
| AU6719387A (en) | 1987-07-09 |
| CA1297105C (en) | 1992-03-10 |
| NO870049L (en) | 1987-07-08 |
| IL81179A0 (en) | 1987-08-31 |
| ES2059360T3 (en) | 1994-11-16 |
| EP0231996A3 (en) | 1988-10-19 |
| DK165692B (en) | 1993-01-04 |
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